1-bromo-4-(bromomethyl)-2-methylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (4-Bromo-3-methylphenyl)methanol (14.4 g, 71.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (26.1 g, 79.0 mmol) is added. The reaction mixture is cooled to 0° C. and PPh3 (20.7 g, 79.0 mmol) is added in small portions. The reaction mixture is stirred 2 h and the triphenylphosphine oxide that forms is filtered off and the solvent removed in vacuo. The resulting semi solid is filtered on a silica gel pad and rinsed with hexane/EtOAc (9:1) to provide the expected product 1-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.39-4.44 (m, 3H) 7.07 (dd, J=8.20, 2.34 Hz, 1H) 7.26 (t, J=1.17 Hz, 1H) 7.49 (d, J=8.20 Hz, 1H) the triphenylphosphine oxide that forms is filtered off the solvent removed in vacuo The resulting semi solid is filtered on a silica gel pad rinsed with hexane/EtOAc (9:1)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Bromo-4-(bromomethyl)-2-methylbenzene (45 of crude from step b, 68.2 mmol) dissolved in CH2Cl2 (500 mL) is mixed and stirred with potassium cyanide (24 g, 364 mmol) and N-tetra(n-butyl)ammonium bromide (1.2 g, 3.64 mmol) in distilled water (500 mL). This reaction mixture is stirred vigorously for 6 h. The organic phase is separated, dried over MgSO4, filtered and concentrated. The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane to provide the expected product 2-(4-bromo-3-methylphenyl)acetonitrile (12.4 g, 87% over two steps) as a clear yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.41 (s, 3H) 3.68 (s, 2H) 7.01 (dd, J=8.50, 2.05 Hz, 1H) 7.21 (d, J=1.37 Hz, 1H) 7.53 (d, J=8.20 Hz, 1H) is mixed The organic phase is separated dried over MgSO4 filtered concentrated The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Bromo-4-(bromomethyl)-2-methylbenzene (45 of crude from step b, 68.2 mmol) dissolved in CH2Cl2 (500 mL) is mixed and stirred with potassium cyanide (24 g, 364 mmol) and N-tetra(n-butyl)ammonium bromide (1.2 g, 3.64 mmol) in distilled water (500 mL). This reaction mixture is stirred vigorously for 6 h. The organic phase is separated, dried over MgSO4, filtered and concentrated. The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane to provide the expected product 2-(4-bromo-3-methylphenyl)acetonitrile (12.4 g, 87% over two steps) as a clear yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.41 (s, 3H) 3.68 (s, 2H) 7.01 (dd, J=8.50, 2.05 Hz, 1H) 7.21 (d, J=1.37 Hz, 1H) 7.53 (d, J=8.20 Hz, 1H) is mixed The organic phase is separated dried over MgSO4 filtered concentrated The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (4-Bromo-3-methylphenyl)methanol (14.4 g, 71.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (26.1 g, 79.0 mmol) is added. The reaction mixture is cooled to 0° C. and PPh3 (20.7 g, 79.0 mmol) is added in small portions. The reaction mixture is stirred 2 h and the triphenylphosphine oxide that forms is filtered off and the solvent removed in vacuo. The resulting semi solid is filtered on a silica gel pad and rinsed with hexane/EtOAc (9:1) to provide the expected product 1-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.39-4.44 (m, 3H) 7.07 (dd, J=8.20, 2.34 Hz, 1H) 7.26 (t, J=1.17 Hz, 1H) 7.49 (d, J=8.20 Hz, 1H) the triphenylphosphine oxide that forms is filtered off the solvent removed in vacuo The resulting semi solid is filtered on a silica gel pad rinsed with hexane/EtOAc (9:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (4-Bromo-3-methylphenyl)methanol (14.4 g, 71.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (26.1 g, 79.0 mmol) is added. The reaction mixture is cooled to 0° C. and PPh3 (20.7 g, 79.0 mmol) is added in small portions. The reaction mixture is stirred 2 h and the triphenylphosphine oxide that forms is filtered off and the solvent removed in vacuo. The resulting semi solid is filtered on a silica gel pad and rinsed with hexane/EtOAc (9:1) to provide the expected product 1-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.39-4.44 (m, 3H) 7.07 (dd, J=8.20, 2.34 Hz, 1H) 7.26 (t, J=1.17 Hz, 1H) 7.49 (d, J=8.20 Hz, 1H) the triphenylphosphine oxide that forms is filtered off the solvent removed in vacuo The resulting semi solid is filtered on a silica gel pad rinsed with hexane/EtOAc (9:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (4-Bromo-3-methylphenyl)methanol (14.4 g, 71.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (26.1 g, 79.0 mmol) is added. The reaction mixture is cooled to 0° C. and PPh3 (20.7 g, 79.0 mmol) is added in small portions. The reaction mixture is stirred 2 h and the triphenylphosphine oxide that forms is filtered off and the solvent removed in vacuo. The resulting semi solid is filtered on a silica gel pad and rinsed with hexane/EtOAc (9:1) to provide the expected product 1-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.39-4.44 (m, 3H) 7.07 (dd, J=8.20, 2.34 Hz, 1H) 7.26 (t, J=1.17 Hz, 1H) 7.49 (d, J=8.20 Hz, 1H) the triphenylphosphine oxide that forms is filtered off the solvent removed in vacuo The resulting semi solid is filtered on a silica gel pad rinsed with hexane/EtOAc (9:1)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 1-bromo-4-(bromomethyl)-2-methylbenzene (631 mg, 2.391 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (516 mg, 68% yield). 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=2.2 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.84 (d, J=9.3 Hz, 1H), 4.42 (s, 2H), 3.78 (s, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.82 (t, J=6.7 Hz, 2HLRMS [ESI, MH+] m/z calcd for C25H33BrNO5S 538.13, found 538.1. The reaction mixture was filtered rinsed alternatively by dichloromethane and methanol The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Bromo-4-(bromomethyl)-2-methylbenzene (45 of crude from step b, 68.2 mmol) dissolved in CH2Cl2 (500 mL) is mixed and stirred with potassium cyanide (24 g, 364 mmol) and N-tetra(n-butyl)ammonium bromide (1.2 g, 3.64 mmol) in distilled water (500 mL). This reaction mixture is stirred vigorously for 6 h. The organic phase is separated, dried over MgSO4, filtered and concentrated. The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane to provide the expected product 2-(4-bromo-3-methylphenyl)acetonitrile (12.4 g, 87% over two steps) as a clear yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.41 (s, 3H) 3.68 (s, 2H) 7.01 (dd, J=8.50, 2.05 Hz, 1H) 7.21 (d, J=1.37 Hz, 1H) 7.53 (d, J=8.20 Hz, 1H) is mixed The organic phase is separated dried over MgSO4 filtered concentrated The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane